EXCHANGE 


29 


[Reprinted  from  the  Journal  of  the  American  Chemical  Society, 
Vol.  XLIII.     No.  12.     December,  1921.J 


Researches  on  Pyrimidines*     XCL     Alkyla- 
tion  of  2-Mercapto-Pyrimidines 


By  William  J.  Horn 


* 


IReprinted  from  the  Journal  of  The  American  Chemical  Society, 
Vol.  XLIII.     No.  12.     December,  1921.] 


[CONTRIBUTION  FROM  THE  DEPARTMENT  OF  CHEMISTRY,  YALE  UNIVERSITY.  ] 
RESEARCHES    ON    PYRIMIDINES.    XCI.   ALKYLATION    OF    2- 
MERCAPTO-PYRIMIDINES. 

BY  WlU<IAM  J.  HORN.1 
Received  July  28,   1921. 

When  a  2-mercapto-6-oxypyrimidine  combination  is  subjected  to  alky- 
lation  in  alkaline  solution,  it  is  susceptible  to  attack  in  three  different 
positions  and,  at  the  present  time,  we  have  no  law,  or  rule,  which  will 
permit  one  to  predict  the  configuration  most  likely  to  be  formed. 

NH— CO 

I  I 
RSC        CH 

II  II 
N CH 

In  most  of  the  cases  so  far  examined2  where  the  radical,  R,  of  the  2-mer- 

1  This  paper  was  constructed  from  a  dissertation  presented  by  William  John  Horn 
to  the  Faculty  of  the  Graduate  School  of  Yale  University,  in  June,  1921,  in  candidacy 
for  the  degree  of  Doctor  of  Philosophy.  (T.  B.  Johnson). 

1  Johnson  and  Clapp,  J.  Biol.  Chem.,  5,  51  (1908) ;  Johnson  and  Heyl,  Am.  Chem.  J., 
37,  628  (1907);  Wheeler  and  Johnson,  ibid.,  42,  30  (1909);  Johnson  and  Jones,  ibid., 
40,  538  (1908);  Johnson  and  Derby,  ibid.,  40,  444  (1908);  Wheeler  and  McFarland, 
ibid.t  42,  101  (1909);  Wheeler  and  Liddle,  THIS  JOURNAL,  30,  1152  (1908);  Johnson  and 
Zee,  Am.  Chem.  J.,  49,  287  (1913). 


2604  WIU,IAM  J.  HORN. 

capto  group  has  been  strongly  positive  in  nature,  the  alkylation  reactions 
have  been  productive  quite  generally  of  isomeric  1-  and  3-nitrogen  sub- 
stituted pyrimidines,  and  there  seems  to  be  no  regularity  in  the  proportion 
in  which  such  isomers  are  produced.  Regarding  the  mechanism  of  these 
reactions  we  have  no  very  positive  evidence,  but  it  has  been  assumed 
as  very  probable,  that  all  these  changes  take  place  primarily  by  addition 
of  the  alkyl  halide  to  the  sodium  salt  of  the  pyrimidine,  which  is  followed 
by  dissociation  of  the  resulting  polymolecular  combination  giving  the  al- 
kylated  pyrimidine  as  the  final  product  of  reaction.  The  configuration 
obtained  will  depend  entirely  upon  the  constitution  of  the  primary  ad- 
dition product. 

In  some  cases,  however,  it  has  been  observed,3'4  especially  when  the 
radical  R  of  the  2-mercapto  group  is  negative  in  character,  that  the  pro- 
duct of  alkylation  is  not  a  nitrogen  pyrimidine  derivative,  but  one  in  which 
the  substitution  of  the  alkyl  group  has  taken  place  on  oxygen  in  the  6- 
position  of  the  pyrimidine  cycle  with  formation  of  an  alkoxyl  or  imido 
ester  combination.  Such  transformations  may  be  interpreted  as  taking 
place  through  direct  substitution,  although  it  is  not  improbable  that  the 
addition  theory  of  reaction  may  apply  also  in  these  cases.  In  fact,  the 
results  obtained  by  Johnson  and  Moran4  on  pyrimidine  alkylations, 
where  alcoholysis  of  imido  ester  combinations  was  observed  to  take  place, 
would  seem  to  be  very  strong  evidence  in  support  of  the  fact  that  we  have 
to  deal  with  intermediate  addition  products  in  this  type  of  change  also. 

We  now  describe  in  this  paper  another  series  of  alkylation  experiments 
which  have  revealed  further  abnormalities  in  chemical  behavior  during 
the  process  of  alkylation.  We  have  substituted  the  negative  radical, 
^-nitrobenzyl,  NOsCeHiCHs  for  R  and  synthesized  the  mercapto-pyri- 
midine  represented  by  Formula  I.  This  compound  is  easily  prepared 
by  the  action  of  ^-nitrobenzyl  chloride  on  the  sodium  salt  of  2-thio-4- 
methyluracil. 

Alkylation  of  this  2-mercapto-pyrimidine  (I)  with  methyl  iodide  leads 
to  the  formation  of  two  products  which  are  not  isomeric.  The  data  thus 
far  obtained  indicate  that  the  methyl  group  substitutes  in  methyl  alcohol 
solution  to  give  only  one  product,  namely,  l,4-dimethyl-2-£-nitroben- 
zyl-mercapto-6-oxypyrimidine,  (V).  The  structure  of  this  compound 
was  established  by  its  behavior  on  hydrolysis  when  it  was  found  to  be 
transformed  smoothly  into  ^-nitrobenzyl  mercaptan  (VII)  and  l,4~di- 
methyluracil  (VI).  We  obtained  no  evidence  of  the  formation  of  an 
isomeric,  3,4-dimethyl-2-£-nitrobenzyl-mercapto-6-oxypyrimidine  or  an 
imido  ester  combination  resulting  from  substitution  on  oxygen  in  the  6- 
position  of  the  ring. 

1  Johnson  and  Haggard,  THIS  JOURNAL,  37,  177  (1915). 
4  Johnson  and  Moran,  ibid.,  37,  2591  (1915). 


AI,KYI.ATION  OF  MBRCAPTO-PYRIMIDINES. 


2605 


c^-c 

re"4wH2s«      MH 
N — 0. 


CH3 


CH3N 


-co 


CO     CH       -f 


C  ,CH 


(I) 

i 

N=COC2H5 
H02C6H4CH2SC     CH  NO^JgH^HgSC       CH 

N— C.CH,  N  —  C.( 

(VTIl) 


H=COCH2CH= 


NH  -  CO 
I  I 

CO  CH 

HH 


H  -  C.CH, 


The  second  product  of  reaction  with  methyl  iodide  proved  to  be  an 
addition  compound,  which  we  have  expressed  by  Formula  II.  Not  only 
is  this  interesting  substance  formed  by  direct  alkylation  of  (I)  with  an 
excess  of  methyl  iodide,  but  the  same  combination  results  also  by  interac- 
tion of  the  pyrimidine  V  with  methyl  iodide  when  digested  in  methyl 
alcohol.  Hydrolysis  of  this  substance  with  hydrochloric  acid  led  to  the 
formation  of  1,4-dimethyluracil  (VI),  proving  that  the  second  methyl 
group  does  not  link  itself  to  nitrogen.  The  choice  between  the  two  other 
possible  linkings,  namely,  addition  to  sulfur  of  the  mercapto  group  or 
oxygen  in  the  6-position  of  the  ring  was  indicated  by  the  behavior 
on  hydrolysis.  By  this  treatment  the  mercapto  group  of  the  addition 
compound  was  replaced  and  identified  as  ^-nitrobenzyl  disulfide  (IV). 
This  sulfide  is  formed  by  oxidation  of  nitrobenzyl  mercaptan,  a  change 
that  is  brought  about  by  the  influence  of  traces  of  iodine  also  formed  as 
a  product  of  hydrolytic  change.  In  other  words,  we  obtained  no  evidence 
of  the  formation  by  hydrolysis  of  the  sulfide  NC^CeH^CI^SCHs.* 

'  The  study  of  these  addition  compounds  will  receive  attention  in  the  immediate 
future.     (T.  B.  J.) 


2606  WILUAM  J.  HORN. 

This  is  the  first  case  to  be  described  where  we  have  been  able  to  isolate 
an  addition  product  of  this  type,  and  the  result  indicates  that  such  combi- 
nations have  probably  resulted  in  previous  condensations  and  that  their 
formation  is  a  partial  explanation  of  the  low  yields  and  abnormal  results 
obtained  in  many  cases.  Johnson  and  Jones8  have  shown  that  the  pyri- 
midine,  2-ethyl-mercapto-3-methyl-5-ethoxy-6-oxypyrimidine,  combines 
with  potassium  iodide  to  form  a  characteristic  addition  product.  Our 
addition  product,  II,  was  absolutely  free  from  inorganic  material. 

The  fact  that  iodine  is  formed  by  hydrolysis  of  the  addition  product 
(II)  in  acid  solution  is  strong  evidence  that  the  alkyl  halide  has  dissociated 
in  the  process  of  addition  to  the  pyrimidine  and  this  condition  is  expressed 
by  the  structural  formula  assigned.  The  identification  of  this  addition 
product  is  strong  evidence  in  support  of  the  assumption  that  all  these 
alkylations  in  the  pyrimidine  series  probably  operate  through  the  inter- 
mediate formation  of  addition  compounds. 

Ethyl  bromide  and  allyl  bromide  interact  with  the  sodium  salt  of  the 
mercapto-pyrimidine  in  an  entirely  different  manner  from  methyl  iodide. 
In  neither  case  did  we  observe  the  formation  of  nitrogen-substituted 
derivatives,  but  both  halides  interacted  to  form  imido  ester  combinations. 
The  structures  of  these  compounds  are  expressed  by  Formulas  VIII  and 
IX  respectively.  The  constitution  of  both  of  these  pyrimidines  was 
established  by  the  fact  that  they  underwent  hydrolysis  with  formation  of 
4-methyluracil  and  nitrobenzyl-mercaptan. 

In  the  experimental  part  of  this  paper  are  recorded  some  new  facts  bear- 
ing on  the  chemistry  of  p-nitrobenzyl-mercaptan  and  its  corresponding 
sulfide  derivatives. 

Experimental  Part. 

2-Thio-4-methyluracil  and  £-Nitrobenzyl  Chloride. — The  method  employed  for 
the  preparation  of  2-thio-4-methyluracil  was  that  used  by  Wheeler  and  McFarland;7 
£-nitro-benzyl  chloride  was  prepared  according  to  the  directions  of  Alway.8 

2-/?-Nitrobenzyl-mercapto-4-methyl-6-oxypyrimidine.  (I). — This  pyrimidine  was 
obtained  in  quantity  by  the  action  of  £-nitrobenzyl  chloride  upon  the  sodium  salt  of 
2-thio-4-methyl-uracil. 

To  sodium  ethylate  solution,  prepared  by  dissolving  a  molecular  proportion  of 
sodium  in  absolute  alcohol,  finely  pulverized  2-thio-4-methyl-uracil  was  added.  On 
heating  this  mixture  for  two  hours  and  shaking  occasionally,  the  sodium  salt  separated 
an4  the  solution  became  reddish-yellow  in  color.  £-Nitrobenzyl  chloride  was  then 
added  and  the  resulting  solution  was  heated  until  it  became  neutral.  The  solution, 
turned  green  at  first  and  then  dark  red.  After  it  had  been  heated  for  about  20  minutes 
it  solidified  to  a  white  cake.  At  the  end  of  the  reaction,  the  mixture  was  cooled,  filtered 
with  the  aid  of  suction  and  the  crystalline  product  was  treated  with  cold  water  to  dis- 
solve the  sodium  chloride  formed  in  the  reaction.  The  yield  of  crude  pyrimidine  was 

•  Johnson  and  Jones,  THIS  JOURNAL,  31,  590  (1909). 

7  Wheeler  and  McFarland,  Ref.  2. 

8  Alway,  THIS  JOURNAL,  24,  1060  (1902). 


OF  MERCAPTO-PYRIMIDINES.  2607 

93%.  This  compound  is  only  slightly  soluble  in  hot  alcohol  and  difficultly  soluble  in 
hot  water.  It  was  purified  by  recrystallization  from  glacial  acetic  acid,  from  which  it 
separated  in  the  form  of  resets  of  colorless  needles.  These  were  collected  on  a  filter, 
washed,  first  with  a  little  acetic  acid  and  then  with  water,  and  dried  at  115°  for  10  to 
15  hours.  By  this  procedure,  an  80%  yield  of  the  pure  compound  was  obtained;  it 
melted  at  220°  to  give  a  clear  yellow  oil. 

Analyses.  Calc.  for  C12HnO3N3S:  N,  15.16;  S,  11.55.  Found:  N,  15.24,  15.6; 
S,  11.42. 

Alkylation  of  2-/>-Nitrobenzyl-mercapto-4-methyl-6-oxypyrimidine. 
Action  of  Methyl  Iodide. 

To  a  sodium  methylate  solution,  made  by  dissolving  a  molecular  proportion  of 
sodium  in  methyl  alcohol,  finely  pulverized  2-/>-nitrobenzyl-mercapto-4-methyl-6- 
oxypyrimidine  was  added  and  the  clear  greenish-yellow  solution  thus  obtained  was 
heated  for  one  hour.  By  means  of  a  dropping  funnel,  slightly  more  than  the  calculated 
quantity  of  methyl  iodide  was  then  added  slowly  to  the  warm  solution  of  the  sodium 
salt  and  the  solution  was  heated  until  it  became  neutral.  Upon  removal  of  the  alcohol 
by  evaporation  under  diminished  pressure,  a  greenish-yellow  solid  separated  which  had 
the  odor  of  parsnips.  This  product  was  triturated  with  cold  water  to  dissolve  sodium 
iodide,  and  the  insoluble  material  collected  on  a  filter  was  dried  in  a  vacuum  desiccator 
over  sulfuric  acid  for  several  days.  This  substance  gave  a  very  strong  test  for  iodine 
on  treatment  with  sulfuric  acid.  When  the  finely  pulverized  product  was  extracted  in  a 
Soxhlet  apparatus  with  dry  ether  free  from  alcohol  for  25  hours,  it  was  separated  into 
two  distinct  compounds,  one  of  which  (^4)  was  soluble  in  ether,  and  the  other  (B)  in- 
soluble. 

(A)  l,4-Dhnethyl-2-^-nitrobenzyl-mercapto-6-oxypyriniidme.  (V). — On  evapo- 
rating the  ether  solution  containing  the  soluble  compound  (A  ]  to  dryness  in  the  air,  a 
yellow  solid  was  obtained  which  represented  71.5%  of  the  weight  of  the  total  alkylated 
products.  This  compound  was  free  from  iodine  and  melted  between  90  °  and  111°.  Upon 
recrystallization  from  glacial  acetic  acid,  it  was  obtained  in  the  form  of  resets  of  white 
needles  which  melted  sharply  at  136°  to  give  a  clear  yellow  oil.  It  was  identified  as  a 
monomethyl  derivative  of  the  original  pyrimidine. 

Analyses.    Calc.  for  Ci3H13O3N3S:   N,  14.4.     Found:   14.14,  14.16. 

HYDROLYSIS  WITH  HYDROCHLORIC  ACID. — The  structure  of  this  compound 
was  established  by  its  behavior  on  hydrolysis  with  cone,  hydrochloric  acid.  One  to 
three  g.  of  the  compound  was  digested  in  100  cc.  of  the  acid  for  several  hours.  In  about 
10  minutes,  the  boiling  solution  became  turbid  and  a  yellowish-brown  oil  separated  on  the 
surface  of  the  liquid.  At  the  end  of  the  reaction  period,  the  solution  was  filtered  to  re- 
move the  oil  and  the  filtrate  evaporated  to  dryness.  By  this  procedure,  a  yellowish- white 
residue  was  obtained  which  melted  at  256-258° ;  the  yield  was  nearly  quantitative  for  1,4- 
dimethyluracil.  After  recrystallization  from  hot  water  and  treatment  with  Norite, 
the  substance  was  obtained  in  the  form  of  colorless  prismatic  needles  free  from  sulfur. 
These  crystals  melted  sharply  at  259-260°  to  give  a  clear  red  oil. 

Analyses.    Calc.  for  C6H8O2N2:  N,20.0.     Found:  19.93,19.72. 

The  yellowish-brown  oil  insoluble  in  water  solidified  as  it  cooled  to  give  a  pearl-white 
solid.  Dried  in  a  vacuum  desiccator  over  sulfuric  acid  the  substance  was  obtained  in 
quantity  corresponding  very  closely  to  the  quantitative  yield  for  ^-nitrobenzyl-mercap- 
tan .  This  compound  is  only  very  slightly  soluble  in  water,  but  is  very  soluble  in  ether.  It 
was  purified  by  recrystallization  from  alcohol  from  which  it  separated  in  the  form  of 
white  transparent  plates  melting  sharply  at  58°  to  a  clear  yellow  oil.  A  molecular  n 
weight  determination  was  made  by  the  freezing-point  method. 


2608  WILLIAM  J.  HORN. 

Analyses.  Calc.  for  C7H7O2NS:  N,  8.28;  S,  18.93;  Mol.  wt.,  169.0.  Found:  N, 
8.13,  8.47;  S,  18.54;  Mol.  wt.,  160.2,  164.8. 

A  further  description  of  this  compound  is  given  below  in  the  section  devoted  to 
the  chemistry  of  nitrobenzyl-mercaptan. 

(B)  The  Addition  Product  of  Methyl  Iodide  and  l,4-Dimethyl-2-/>-nitrobenzyl- 
mercapto-6-oxypyrimidine.  (II). — The  insoluble  amorphous  compound  (B)  which  was 
yellowish-brown  in  color,  was  observed  to  turn  red  slowly  on  exposure  to  the  air,  a 
behavior  which  was  due  evidently  to  the  liberation  of  iodine.  After  drying  this  com- 
pound in  a  vacuum  desiccator  over  sulfuric  acid  for  several  days,  the  weight  was  found 
to  correspond  to  28%  of  the  weight  of  the  total  alkylated  products.  In  a  repetition 
of  the  alkylation  with  methyl  iodide  with  a  quantity  of  the  iodide  greater  than  that 
previously  used,  as  high  as  50%  of  the  insoluble  addition  compound  was  obtained  in 
this  reaction.  This  product  did  not  melt  sharply;  the  melting  point  ranged  between 
79°  and  136°.  It  gave  a  very  strong  test  for  iodine  when  treated  with  sulfuric  acid  and 
left  no  residue  when  heated  on  platinum  foil.  When  boiled  in  50%  alcohol,  it  was  found 
to  dissociate,  and  the  cool  solution  deposited  white  needle-like  crystals.  The  com- 
pound formed  melted  at  136°  and  was  identified  as  l,4-dimethyl-2-£-nitrobenzyl-mer- 
capto-6-oxypyrimidine. 

The  addition  compound  was  purified  by  dissolving  it  to  saturation  in  hot  80% 
alcohol,  filtering  off  any  undissolved  material  and  cooling  the  solution  immediately 
in  an  ice-bath,  with  stirring.  By  this  procedure  the  compound  was  obtained  in  the 
form  of  a  light  brown  colloidal  precipitate.  It  was  collected  and  washed  with  a  little 
80%  alcohol,  and  dried  in  a  vacuum  desiccator  over  sulfuric  acid  for  several  days. 
Yield,  61%.  It  melted  between  65-75°  with  slight  decomposition. 

Analyses.     Calc.   for  Ci4H18O3N,SI:    N,   9.69.     Found:    9.50,9.39. 

HYDROLYSIS  WITH  HYDROCHLORIC  ACID. — From  1  to  5  g.  of  the  addition  compound 
was  hydrolyzed  by  digestion  with  50  cc.  of  cone,  hydrochloric  acid  for  several 
hours.  During  this  operation  a  yellowish-brown  oil  separated  which  solidified  immedi- 
ately when  cooled.  The  yellow  solution  was  then  filtered  and  the  residue  dried  and  saved. 
This  compound  was  identified  as  £-nitrobenzyl  disulfide.  The  yield  was  nearly  quan- 
titative. Two  recrystallizations  from  alcohol  gave  a  product  which  separated  in  the 
form  of  colorless  needles  melting  at  126°  to  give  a  clear  yellow  oil.  A  molecular- weight 
determination  was  made  by  the  boiling-point  method. 

Analyses.  Calc.  for  CnH^CUNzS*:  N,  8.33;  S,  19.05;  Mol.  wt.,  336.0.  Found: 
N,  8.02,  8.34;  S,  19.02,  19.09;  Mol.  wt.,  334.5,  346.2. 

A  further  description  of  this  compound  and  its  properties  is  given  in  the  section 
dealing  with  the  chemistry  of  p-nitrobenzyl-mercaptan. 

The  yellow  acid  filtrate  was  extracted  several  times  with  ether.  On  evaporating 
the  solvent  a  crystalline  solid  was  obtained  which  was  identified  as  free  iodine. 

When  the  filtrate  from  the  ether  extractions  was  evaporated  to  dryness,  a  grayish- 
black  solid  was  obtained.  The  residue  was  treated  with  a  little  cold  alcohol  to  remove 
traces  of  iodine,  and  then  recrystallized  twice  from  hot  water  and  decolorized  by  treat- 
ment with  Norite.  As  the  solution  cooled,  the  compound  separated  in  the  form  of  white 
prismatic  needles.  The  melting  point,  259-260°,  indicated  that  we  were  dealing  with 
dimethyluracil. 

When  the  pyrimidine,  l,4-dimethyl-2-£-nitrobenzyl-mercapto-6-oxypyrimidine 
(A)  was  hydrolyzed  with  cone,  hydrochloric  acid  to  which  a  little  free  iodine  had  been 
added,  the  results  were  similar  to  those  obtained  by  hydrolysis  of  the  above  addition 
compound.  That  is,  £-nitrobenzyl  disulfide  and  1,4-dimethyluracil  were  formed 
in  this  reaction. 

Synthesis  of  the  Addition  Product  from  its  Components. — To  synthesize  the  addition 


ALKYLATION  OF  MERCAPTO-TYRrMlW*n£S..  '  2609 

compound,  methyl  iodide  (3  moles)  was  added  to  a  warm  alcohol  solution  of  1,4-dimethyl- 
2-£-nitrobenzyl-mercapto-6-oxypyrimidine  and  the  solution  was  boiled  for  12  hours. 
As  it  cooled,  yellow  needle-like  crystals  separated.  These  were  found  to  be  free  from 
iodine  and  after  recrystallization  from  glacial  acetic  acid,  melted  at  136  °,  which  corre- 
sponds to  the  melting  point  of  the  unaltered  mercapto-pyrimidine.  After  the  removal  of 
the  methyl  alcohol  and  methyl  iodide  from  the  nitrate  by  distillation,  a  light  brown  prod- 
uct was  obtained.  This  gave  a  very  good  test  for  iodine.  Digestion  with  hydrochloric 
acid  transformed  it  smoothly  into  £-nitrobenzyl  disulfide,  which  melted  at  135.5°, 
and  1,4-dimethyluracil,  melting  at  260°. 

Alkylation  with  Ethyl  Bromide. 

2-^-Nitrobenzyl-mercapto-4-methyl-6-ethoxy-pyrimidine.  (VIII). — 2-£-Nitroben- 
zyl-mercapto-4-methyl-6-oxypyrimidine  was  added  to  a  sodium  ethylate  solution  made 
by  dissolving  a  molecular  proportion  of  sodium  in  absolute  alcohol,  and  the  solution 
was  heated  for  3  hours.  A  little  more  than  the  molecular  quantity  of  ethyl  bromide 
was  then  added  slowly  through  a  dropping  funnel  and  the  solution  was  heated  until  it 
became  neutral.  The  hot  solution  was  filtered  to  remove  sodium  bromide,  and  as  the 
filtrate  cooled,  resets  of  needle-like  crystals  separated.  After  filtering  and  treating 
the  residue  with  a  little  water  to  remove  any  traces  of  sodium  bromide,  the.  above 
pyrimidine  was  obtained;  it  melted  between  90°  and  96°.  Recrystallization  from  al- 
cohol gave  a  product  which  melted  sharply  at  104°.  Yield,  about  32%. 

Analyses.     Calc.  for  CuHuOgNsS:    N,  13.77.     Found:    13.70,  13.90. 

HYDROLYSIS  WITH  HYDROCHLORIC  ACID. — From  1  to  3  g.  of  this  compound 
was  hydrolyzed  by  digestion  with  100  cc.  of  cone,  hydrochloric  acid  for  3  hours. 
The  solution  was  filtered  to  remove  the  oil  which  separated  and  evaporated  to  dryness, 
yielding  a  yellowish-white  solid.  This  compound  was  identified  as  4-methyluracil.  It 
was  obtained  in  the  form  of  white  prismatic  needles  which  crystallized  from  water  and 
did  not  melt  below  300°.  The  yield  was  quantitative. 

Analyses.     Calc.  for  C5H6O2N2:    N,  22.22.     Found:    22.24,  22.38. 

When  the  oily  product  formed  in  this  reaction  was  cooled,  it  solidified  to  form  a 
pearl-white  solid  which  corresponded  in  quantity  very  closely  to  the  calculated  yield 
for  ^-nitrobenzyl-mercaptan.  After  recrystallization  from  alcohol,  it  was  obtained 
in  the  form  of  white  transparent  plates  melting  at  57°  to  give  a  clear  yellow  oil.  A 
mixture  of  this  compound  with  £-nitrobenzyl-mercaptan  obtained  in  a  previous  ex- 
periment melted  at  57-58°. 

Alkylation  with  Allyl  Bromide. 

2-p-Nitrobenzyl-mercapto-4-methyl-6-alloxy-pyrimidine.  (IX) . — To  sodium  ethyl- 
ate  solution  made  by  dissolving  a  molecular  proportion  of  sodium  in  absolute  alcohol, 
2-/>-nitrobenzyl-mercapto-4-methyl-6-oxypyrimidine  was  added  and  the  solution  was 
heated  for  2^  hours.  Allyl  bromide  (1  mol.)  was  then  added  slowly  through  a  dropping 
funnel  and  the  resulting  solution  was  heated  until  it  became  neutral.  On  removal  of 
the  alcohol  by  distillation,  a  soft,  sticky,  dark  red  solid  separated.  This  was  dried  in  a 
vacuum  desiccator  over  sulfuric  acid  for  several  days,  and  then  extracted  in  a  Soxhlet 
apparatus  with  dry  ether  free  from  alcohol.  By  this  procedure  two  compounds  were 
obtained;  a  compound  insoluble  in  ether,  which  proved  on  purification  to  be  unaltered 
material,  and  a  compound  soluble  in  ether. 

When  ether  solution  of  the  soluble  compound  was  evaporated  to  dryness  in  the  air, 
a  reddish-yellow  residue  was  obtained.  After  two  recrystallizations  from  ligroin  the 
compound  was  isolated  in  the  form  of  light  yellow  needles  which  melted  at  77-78°  to 
form  a  clear  yellow  oil. 


2610  '   WILUAM  J.  HORN. 


Analyses.     Calc.  for  C^HisOaNsS:    N,  13.25.     Found:    13.42,  13.52. 

HYDROLYSIS  WITH  HYDROCHLORIC  ACID.—  A  small  quantity  of  this  compound 
was  hydrolyzed  by  digestion  with  100  cc.  of  cone,  hydrochloric  acid  for  1  */«  hours. 
The  hot  solution  was  filtered  to  remove  the  oil  which  separated  and  the  filtrate  was 
evaporated  to  dryness.  A  nearly  quantitative  yield  of  4-methyluracil  was  thus  ob- 
tained which,  on  recrystallization  from  water,  did  not  melt  below  300°. 

By  recrystallization  of  the  oily  product  from  alcohol,  white  transparent  plates 
were  obtained  which  melted  at  57°  to  give  a  clear  yellow  oil. 

The   Chemistry  of  ^-Nitrobenzyl-mercaptan. 

When  we  endeavored  to  identify  ^-nitrobenzyl  mercaptan  (NO2C6H4- 
CH2SH),  formed  in  the  hydrolysis  of  some  of  the  2-mercapto-pyrimidines, 
unexpected  results  were  obtained.  We  obtained  a  product  which  melted 
consistently  at  58°,  while  the  melting  point  assigned  to  this  compound 
in  the  literature  is  140°.  This  marked  discrepancy  led  us,  therefore, 
to  an  investigation  of  the  properties  of  this  mercapto  compound  and  its 
corresponding  sulfide  derivatives.  We  found  that  our  product  melting 
at  58°  gave  analytical  results  in  complete  agreement  with  those  required 
for  the  mercaptan.  When  this  compound  was  subjected  to  oxidation 
in  the  presence  of  iodine,  or  with  potassium  permanganate,  or  air  in  the 
presence  of  ammonia,  it  was  transformed  into  the  disulfide  (NO2C6H4CH2)2S2 
melting  at  126.5°.  Price  and  Twiss9  give  the  melting  point  of  this 
compound  as  126.5°.  It  was  prepared  by  these  chemists  by  the  action 
of  sodium  carbonate  upon  ^-nitrobenzyl  thiosulfate. 

Strakosch,10  who  investigated  the  preparation  of  £-nitrobenzyl-mercap- 
tan,  prepared  it  by  the  action  of  potassium  hydrosulfide  and  ammonium 
sulfide  upon  ^-nitrobenzyl  chloride  and  states  that  these  reactions  lead 
to  the  formation  of  /?-nitrobenzyl-mercaptan  melting  at  140°.  He  also 
states  that,  in  the  case  of  the  action  of  ammonium  sulfide  upon  p-nitro- 
benzyl  chloride,  prolonged  boiling  leads  to  the  formation  of  p-mtro- 
benzyl  disulfide  which  he  describes  as  melting  at  89°.  On  repeating  his 
work,  with  potassium  hydrosulfide  as  a  reagent,  it  was  impossible  to  iso- 
late any  of  the  compounds  which  he  describes.  Furthermore,  it  was  found 
that  ammonium  sulfide  reacts  with  ^-nitrobenzyl  chloride  in  alcoholic 
solution  to  give  only  the  sulfide  (NO2C6H4CH2)2S  melting  at  158-159°. 

WTien  ^-nitrobenzyl  chloride  was  treated  with  sodium  hydrosulfide 
in  alcoholic  solution,  we  obtained  two  compounds;  the  disulfide  melting 
at  126°,  and  the  sulfide  melting  at  158-159°.  This  compound  corre- 
sponds to  ^-nitrobenzyl  sulfide  described  by  O.  Fischer.11 

The  interesting  results  obtained  with  ^-nitrobenzyl-mercaptan  raise  the 
question  whether  the  corresponding  ortho  and  meta  isomers  of  this  mercapto 
compound  have  been   correctly   described. 
9  Price  and  Twiss,  J.  Chem.  Soc.,  93,  1401  (1908). 
10  Strakosch,  Ber.t  5,  698  (1872). 
"  O.  Fischer,  ibid.,  28,  1338  (1895). 


"***:•*:  •:'  •  •*• 

YRiMiDixrvS.  2611 

Summary. 

1.  Methyl  iodide  interacts  with  the  sodium  salt  of  2-£-nitrobenzyl- 
mercapto-4-methyl-6-oxypyrimidine  to  give  first  a  nitrogen  substituted 
derivative,  which  then  interacts  with  another  molecule  of  methyl  iodide 
to  form  an  addition  product.     The  methyl  group  substitutes  in  the  1- 
position  of  the  pyrimidine  ring. 

2.  Ethyl   bromide   and   allyl   bromide   interact   with   the   mercapto- 
pyrimidine  in  a  manner  entirely  different  from  that  with  methyl  iodide. 
In  both  of  these  cases,  an  oxygen  ether  is  formed,  and  no  evidence  was  ob- 
tained of  substitution  of  the  alkyl  groups  on  a  nitrogen  atom  of  the  pyrim- 
idine  ring. 

3.  In   the   hydrolysis   of    2-^-nitrobenzyl-mercapto-pyrimidines   with 
acids,  ^-nitrobenzyl-mercaptan  is  formed  melting  at  57-58°.     If,  however, 
free  iodine  functions  during  hydrolysis,  this  mercaptan  is  destroyed  and 
the  disulfide,  melting  at  126.5°,  is  formed  by  oxidation. 

4.  The  literature  concerning   ^-nitrobenzyl-mercaptan    is    incorrect; 
in  this  paper  the  melting  points  of  this  compound,  its  disulfide  and  corre- 
sponding monosulfide  are  described  correctly. 

NEW  HAVEN,  CONNECTICUT. 


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